Axonal degeneration is a common feature of many neurological diseases including neurodegenerative disorders, hereditary neuropathies, traumatic injury, diabetes, glaucoma, and chemotherapy-induced neurotoxicity. Axonal dysfunction is an early event in many of these disorders, and so axo-protective therapies are a central focus for the development of new treatments for these conditions. Recent studies demonstrate that axonal degeneration is an active and highly regulated process, yet the intrinsic, neuronal mechanism promoting degeneration is poorly understood. Expression of Nmnat is the most potent axo-protective strategy yet identified. The ability of Nmnat to protect axons following a wide range of insults in both mammals and Drosophila indicates that it modulates a fundamental, evolutionarily conserved axonal degeneration pathway. However the identity of this pathway is unknown. We have developed novel, large-scale screening paradigms in both mammalian neurons and Drosophila that will allow us to identify genes required for Nmnat-dependent axonal protection as well as genes that promote axonal degeneration following injury. We propose to explore the potential of these new assays to identify genes that are crucial for the prevention of axonal degeneration and, as such, may have therapeutic potential in neurological disorders where axonopathy is a major contributor. By performing these complementary genetic screens, we hope to identify a larger cohort of genes involved in the evolutionarily conserved axonal degeneration process than would likely be found using any individual screen. It is our expectation that findings derived from these exploratory studies will allow our labs as well as others throughout the world to make rapid progress in understanding the process of axonal loss in disease. PUBLIC HEALTH RELEVANCE: This research is relevant to public health because it will identify components of pathways that promote axonal degeneration following injury and disease. Axonal degeneration is a prominent component of many neurological disorders including neurodegenerative diseases, hereditary neuropathies, trauma, diabetes, glaucoma, and chemotherapy-induced neurotoxicity. Identifying components of the pathways in axons that promote degeneration will provide insights into the fundamental mechanism underlying axonal degeneration as well as potential therapeutic targets for the many neurological diseases characterized by axonal degeneration.